MicroRNA-29a-c decrease fasting blood glucose levels by negatively regulating hepatic gluconeogenesis

J Hepatol. 2013 Mar;58(3):535-42. doi: 10.1016/j.jhep.2012.10.024. Epub 2012 Oct 27.

Abstract

Background & aims: The expression levels of microRNA-29 (miR-29) family members (miR-29a, miR-29b, miR-29c, here denoted collectively as miR-29a-c) are increased in livers of Goto-Kakizaki diabetic rats and db/db diabetic mice. However, the functional consequences of miR-29a-c upregulation in diabetic livers are not explored. The objective of this study was to evaluate the roles of miR-29a-c in the regulation of hepatic glucose production and blood glucose levels using different mouse models.

Methods: db/m, db/db diabetic and diet-induced obese (DIO) mice were injected with adenovirus expressing miR-29a-c through the tail vein. Blood glucose levels were measured and glucose-tolerance tests and pyruvate-tolerance tests were performed. To explore the molecular mechanism by which miR-29a-c regulate hepatic glucose metabolism, gain or loss of miR-29a-c function studies were performed in primary mouse hepatocytes and the direct effectors of miR-29-mediated effects on glucose metabolism were identified.

Results: Adenovirus-mediated overexpression of miR-29a-c in the livers of db/m, db/db, and DIO mice decreased fasting blood glucose levels and improved glucose tolerance. Overexpression of miR-29a-c in primary hepatocytes and mouse livers decreased the protein levels of PGC-1α and G6Pase, the direct targets of miR-29a-c, thereby reducing cellular, and hepatic glucose production. In contrast, loss of miR-29a-c function in primary hepatocytes increased the protein levels of PGC-1α and G6Pase and increased cellular glucose production. Finally, enforced expression of PGC-1α increased miR-29a-c expression levels in primary hepatocytes, thus forming a negative feedback regulation loop.

Conclusions: miR-29a-c can regulate hepatic glucose production and glucose tolerance in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis*
  • Colforsin / pharmacology
  • Dexamethasone / pharmacology
  • Fasting / metabolism*
  • Gluconeogenesis*
  • Glucose-6-Phosphatase / genetics
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / physiology*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Rats
  • Trans-Activators / genetics
  • Transcription Factors

Substances

  • Blood Glucose
  • MIRN29 microRNA, mouse
  • MIRN29 microRNA, rat
  • MicroRNAs
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Colforsin
  • Dexamethasone
  • Glucose-6-Phosphatase